Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen

Abstract

Abstract.Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter II in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 postmenopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters I.3, II and I.7 of the aromatase gene of which promoter I.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter I.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target

“…In order to find suitable models to test our vaccine, we screened several tumor cell lines, and in line with FOXL2 expression restriction in female organs, we found only modest levels of Foxl2 cDNA in 2 ovarian cancer cell lines (BR5 and ID8) and 1 breast cancer cell line (4T1). The latter observation is in agreement with a study by Wegman et al, who demonstrated that FOXL2 is expressed in some breast cancer patients ( 21 ). Because of the very low endogenous level of Foxl2 , we decided to overexpress the mutated form of Foxl2 to generate BR5-FOXL2 and 4T1-FOXL2 cell lines.…”

“…Due to the lack of any suitable GCT model ( 36 ) to test in vivo vaccine’s efficacy, we attempted to identify FOXL2 expression in several tumor cell lines. In line with a FOXL2 expression pattern in human female tissues ( 18 , 21 ), we found a very limited level of Foxl2 cDNA in 2 ovarian cancer cell lines (BR5 and ID8) and 1 breast cancer cell line (4T1) ( Supplemental Figure 6 ). The lack of Foxl2 expression prompted us to overexpress mutated Foxl2 C389G in BR5 and 4T1 cancer cell lines using a pCMV6-A-PURO vector ( Supplemental Figure 4A , right panel).…”

“…Hence, we tested the reactivity of TILs against FOXL2-derived peptides, and we observed that 4 of 7 GCT patients showed spontaneous adaptive response against FOXL2, indicating that FOXL2 is a target of GCT. Given that FOXL2 expression has been reported in some breast ( 21 ) and cervical ( 22 ) cancers, we don’t exclude that, in addition to being a marker and target in GCT, FOXL2 could be a potential target in those malignancies where its expression is elevated. The peptide-based approach facilitates detection of CD8 + and CD4 + T cells, and it has been suggested to provide higher sensitivity in mapping immune dominant epitopes than current prediction software ( 62 ).…”

“…Misregulation of FOXL2 expression and the presence of a highly recurrent somatic mutation C402G (C134W), identified in 90%–97% of GCT ( 1 , 2 ), contributes to the transformation of normal granulosa cells to a malignant state ( 20 ). Interestingly, FOXL2 expression levels increase in GCT ( 20 ), as well as in some breast ( 21 ) and cervical cancers ( 22 ). High expression of FOXL2 correlates with worse overall survival in GCT ( 23 ), possibly due to its antiapoptotic role ( 24 ).…”

FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

“…In mammalian species, new reproductive tissues appeared, including the uterus, placenta and mammary gland. Collectively, our data as well as GEO profiles, NextProt-Beta data and the human protein atlas have documented the expression of FOXL2 in every female reproductive tissue: the oviduct, uterus (endometrium and myometrium), mammary gland and placenta [52,[54][55][56]63,73,88]. Interestingly, whereas FOXL2 is expressed in each reproductive tissue of mammalian female, its regulation varies with the nature of the reproductive tissue.…”